The present invention relates to an improved process for the preparation of thiazolidine-2,4-dione derivatives. More particularly the present invention relates to an improved process for the preparation of 5-[4-[[3-Methyl-4-oxo-3,4-dihydroquinazolin-2-yl]methoxy]benzyl]thiazolidine-2,4-dione of the formula (1) and pharmaceutically acceptable salts thereof which are useful as antidiabetic compounds. The thiazolidine-2,4-dione derivative of the formula (1) is particularly useful for the treatment of diabetes type II (NIDDM) and related complications. 
We have in our international publication number WO 97/41097 described the synthesis of the 5-[4-[[3-Methyl-4-oxo-3,4-dihydroquinazolin-2-yl]methoxy]benzyl]thiazolidine-2,4-dione of the formula (1). Compound of the formula (2) on reduction using the expensive catalyst Pd/C in stoichiometric quantity gives the corresponding saturated compound of the formula (3). The ethyl ester of the formula (3) on hydrolysis using methanol/water/sodium carbonate recipe gives the acid of the formula (4) in about 80% yield after a tedious workup sequence involving removal of methanol, then dilution with water, extraction with an organic solvent to remove impurities and then adjustment of pH to precipitate the required acid of the formula (4). The acid of the formula (4) is activated by converting it either to the mixed anhydride of the formula (5) by treating with pivaloyl chloride or the acid chloride of the formula (6) by treating with thionylchloride. Condensation of formula (5) or (6) with N-methyl anthranilamide of the formula (7) gives the amide of the formula (8). Amide of the formula (8) on cyclisation by refluxing in xylene/acetic acid for xcx9c2-30 hours yields about 50% of the cyclised compound of the formula (1). Compound of the formula (1) upon treatment with potassium t-butoxide in methanol gives the corresponding potassium salt of the formula (9). The reaction steps involved in the process are shown in scheme-I below. 
The following are the difficulties encountered during the scaleup trials employing the above said process:
The step of preparing the compound of the formula requires stoichiometric quantities of Pd/C. Nearly 70% of the total cost of the product is due to the use of Pd/C which is very expensive. The time required for the completion of the reaction is about 40 hours, which is also very high and further escalates the cost.
The hydrolysis of compound of formula (3) to give the acid of the formula (4) by using methanol/water/sodium carbonate recipe makes the reaction workup more tedious because it involves removal of methanol, then dilution with water, extraction with an organic solvent to remove impurities and then adjustment of pH to precipitate the required acid of the formula (4), in addition, the reaction time is large, i.e. more than 12 hours. Further the yield is also not very good (80%).
The activation of the acid of the formula (4) by converting to the mixed anhydride of the formula (5) involves use of different chemicals such as pivaloyl chloride, triethylamine and solvents such as dichloromethane, which results in messing-up of the reaction mixture. Further more the conversion of the acid of the formula (4) to the acid chloride of the formula (6) involves the use of corrosive reagents like thionyl chloride. Moreover, the reactions are moisture sensitive.
Because of the large number of chemicals employed in the previous step, the isolation of the intermediate amide of the formula (8) becomes very complicated and also results in low yield (50%) of the amide of the formula (8).
The cyclisation of the intermediate amide of the formula (8) results in low yield (xcx9c50%) of the compound of the formula (1) and the reaction time is large (xcx9c40 hours)
The preparation of potassium salt of the formula (9) employing potassium t-butoxide is not only risky but also expensive thereby making the process uneconomical.
Keeping in view of the above difficulties in the process disclosed in our copending application mentioned above for the preparation of 5-[4-[[3-Methyl-4-oxo-3,4-dihydroquinazolin-2-yl]methoxy]benzyl]thiazolidine-2,4-dione of the formula (1), we directed our research towards developing an improved process which would be cost and time effective, as well as simple for scaling-up.
The main objective of the present invention is, therefore, to provide an improved process for the preparation of 5-[4-[[3-Methyl-4-oxo-3,4-dihydroquinazolin-2-yl]methoxy]benzyl]thiazolidine-2,4-dione of the formula (1) avoiding the above mentioned difficulties.
Another objective of the present invention is to provide an improved process for the preparation of 5-[4-[[3-Methyl-4-oxo-3,4-dihydroquinazolin-2-yl]methoxy] benzyl]thiazolidine-2,4-dione of the formula (1) without employing expensive and hazardous chemicals thereby making the process not only economical but also safe.
Yet another objective of the present invention is to provide an improved process for the preparation of 5-[4-[[3-Methyl-4-oxo-3,4-dihydroquinazolin-2-yl]methoxy]benzyl]thiazolidine-2,4-dione of the formula (1), which involves very simple work-up procedures making the process simple.
We have developed the improved process of the present invention based on our finding that use of Raney-Nickel or magnesium/methanol as reducing agents to reduce the compound of the formula (2xe2x80x2) where R represents a (C1-C4)alkyl group, not only results in the reduction of cost but also results in efficient reduction. In addition, the compound of formula (3xe2x80x2) where R represents a (C1-C4)alkyl group and the compound of formula (4) can also be directly condensed with N-methyl anthranilamide of the formula (7) without preactivation to produce compound of formula (1) which further makes the process simple and economical.
Accordingly the present invention provides an improved process for the preparation of 5-[4-[[3-Methyl-4-oxo-3,4-dihydroquinazolin-2-yl]methoxy]benzyl]thiazolidine-2,4-dione of the formula (1), which comprises:
(a) reducing the compound of the formula (2xe2x80x2) where R represents a (C1-C4)alkyl group using Raney Nickel or Magnesium in alcohol having 1 to 4 carbon atoms or mixtures thereof, and if desired reesterifying using sulphuric acid at a temperature in the range of 0xc2x0 C. to 60xc2x0 C. to obtain a compound of formula (3xe2x80x2) wherein R is as defined above,
(b) hydrolysing the compound of formula (3xe2x80x2) wherein R is as defined above, by conventional methods to obtain the acid of the formula (4),
(c) condensing the acid of the formula (4) with N-methyl anthranilamide of the formula (7) directly without any preactivation of the acid to produce the compound of formula (1) and if desired
(d) converting the compound of formula (1) to pharmaceutically acceptable salts thereof by conventional methods.
According to an embodiment of the present invention, the compound of the formula (3xe2x80x2) wherein R is as defined above, obtained in step (a) may also be condensed directly with N-methyl anthranilamide of the formula (7) to obtain the compound of the formula (1). The reaction is shown in Scheme-II below: 
The reduction of the compound of formula (2xe2x80x2) wherein R is as defined above using 40-130% (w/v) preferably 100% (w/v) Raney Nickel proceeds to completion in 8 to 70 hours, preferably from 12-24 hours, at 15xc2x0 C.-70xc2x0 C. preferably 30xc2x0 C.-60xc2x0 C. and at atmospheric pressure to 600 psi. preferably from atmospheric pressure to 400 psi of hydrogen pressure. The crude material is taken in lower alcohol like methanol, ethanol, propanol and the like and precipitated big adding water thereby affording a highly pure compound of the formula (3xe2x80x2), in about 85-90% overall yield and a purity of about 97-99%. The reduction using magnesium, (4-12 eq., preferably 8-10 eq.) in alcohol having 1 to 4 carbon atoms or their mixtures at a temperature in the range of 10xc2x0 C. to 60xc2x0 C., preferably at a temperature in the range of 15xc2x0 C. to 30xc2x0 C. for about 2-15 hours, preferably from 6-8 hours results in a mixture of the acid of the formula (4) and an ester of the formula (3xe2x80x2) where R is as defined above.
After reacting with magnesian/alcohol having 1 to 4 carbon atoms for 2-15 hours, preferably from 6-8 hours, either water is added and reaction continued to obtain pure compound of formula (4) or sulphuric acid is added till pH is 2 and refluxed for 2-15 hours, preferably for 6-8 hours to produce pure ester of the formula (3xe2x80x2) where R is as defined above. The inorganic salts precipitate out quantitatively in the form of magnesium sulphate. Hence, no dissolved solids get into the effluent. These esters of the formula (3xe2x80x2) upon hydrolysis with aq. sodium hydroxide give the acid of the formula (4) in 97-99% yield and 95-99% purity. The reaction time is drastically reduced to only xcx9c2 hours as compared to 12 hours required by the process disclosed in our above said international publication. Workup is also extremely simplified involving only pH adjustment to obtain the required acid of the formula (4). The acid of the formula (4) is condensed with N-methyl anthranilamide of the formula (7) directly for about 6-20 hours, preferably 10-12 hours to produce the compound of formula (1) without any pre-activation of the acid of the formula (4). The yield is xcx9c70% with a purity of xcx9c99%.
Alternatively the condensation can also be carried out with the esters of formula (3xe2x80x2) where R is as defined above with N-methyl anthranilamide of the formula (7) for a period of 5-30 hours, preferably 6-20 hours to produce the compound of formula (1) albeit in low yield (20%). However, the yield can be improved to a maximum of 60% if the reaction time is increased to 40-50 hours. The resulting compound of formula (1) upon treating with methanolic potassium hydroxide potassium carbonate or potassium t-butoxide, at 60-70xc2x0 C. and cooling the reaction mixture to room temperature and maintaining it for 1 h room temperature, (gives the corresponding potassium salt of the formula (9) in xcx9c90% yield in a pharmaceutically acceptable quality. The reaction may be carried out in the presence of solvents such as xylene/methanol mixture in the ration of 1:1. In a similar manner, other pharmaceutically acceptable salts of the formula (1) can be prepared by conventional methods.
The present invention also envisages an improved process for the preparation of compound of the formula (2) starting from p-hydroxybenzaldehyde of the formula (10) and alkyihaloacetate of the formula (11). This process comprises
a). reacting p-hydroxybenzaldehyde of the formula (10) and alkylhaloacetate of the formula (11) where Hal represents halogen atom like fluorine, chlorine, bromine or iodine and R is as defined earlier in the presence of aromatic hydrocarbon solvents, a base, alkyl or aryl sulphonic acid and iodine to obtain the compound of the formula (12) where R is as defined earlier.
b). condensing the compound of formula (12) where R is as defined earlier with thiazolidine-2,4-dione of the formula (13) in the presence or absence of a solvent using catalysts to produce a compound of formula (2xe2x80x2). The reaction is shown in Scheme-III below: 
The reaction may be carried out in the presence of aromatic hydrocarbon solvent such as benzene, toluene, xylene and the like or mixtures thereof The base such as alkali and alkaline earth metal carbonates and bicarbonates like potassium carbonate, potassium bicarbonate, sodium carbonate, calcium carbonate and the like may be used. The alkyl or aryl sulphonic acid such as methane sulphonic acid, ethane sulphonic acid, propane sulphonic acid, p-toluene sulphonic acid, benzene sulphonic acid, p-nitro benzene sulphonic acid and the like may be used.
We have observed that the use of iodine activates the halo group present in the compound of formula (11) where Hal represents halogen atom like fluorine, chlorine bromine and R is as defined earlier while reflux using a Dean-Stark condenser in the presence of alkyl or and sulphonic acids helps in enhancing the reaction rate. The reaction is complete in 3-10 hours, preferably 5-7 hours under these conditions as compared to xcx9c18 hours as described in the prior art. Moreover, the reaction workup is simplified by addition of water to the reaction mixture followed by separation of solvent layer. The solvent layer is used as such for the next step of condensing the compound of formula (12) where R is as defined earlier with thiazolidine-2,4-dione of the formula (13). Since, water is being removed azeotropically, in this step, no drying of the solvent layer is required. This process not only uses a single, safe solvent but also optionally makes the two-stage process of the preparation of the compound of formula (12) where R is as defined earlier in a single pot operation. The yield and purity of the compound of the formula (12) is also found to be good (80% and 90% respectively).
The condensation of compound of formula (12) with compound of formula (13) may be carried out in the presence or absence of solvents such as toluene, xylene and the like, using catalysts such as benzoic acid, piperidine and the like, at reflux temperature for a period of 6-8 h to give compound of formula (2xe2x80x2) in xcx9c 85% yield.